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					Bioequivalence Guidance Summary                                                                                                                             PHC331H1

 Bioequivalence Guidance Summary
 Enter Drug Name Here

 Regulatory Body           FDA

 Study Design              Single Dose

 Drug Characteristics        Modified Release          Highly Variable Drug
                             Critical Dose Drug        Rapid Onset Drug
                             Long Half-life Drug       Non-Linear Kinetics



 Click here to check the FDA Guidance for Industry: Individual Product Bioequivalence Recommendations

 Standards for Bioequivalence
 Unless otherwise indicated by a specific guidance, this guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic range
 drugs remain unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs. (1)
 [90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2] (1)




 Sampling Scheme Criteria
 We recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs,
 we recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more
 terminal half lives of the drug. The exact timing for sample collection depends on the nature of the drug and the input from the administered dosage form. The
 sample collection can be spaced in such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be
 estimated accurately. At least three to four samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear
 regression. (1) An adequate washout period (e.g., more than 5 half lives of the moieties to be measured) would separate each treatment. (1)



 Fasting and/or Fed Required?
 we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the
 following exceptions:
 • When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high
 permeability (BCS Class I) (see footnote 3), or
 • When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or
 • When the RLD label does not make any statements about the effect of food on
 absorption or administration. (2)

 In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover study. Both treatments should be sprinkled on one of the soft foods mentioned in the
 labeling, usually applesauce. The BE data should be analyzed using average BE and the 90 percent CI criteria should be used to declare BE. If there are questions
 about other foods, the design, or the analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.(2)




                                                                                                                                                     6/12/2013 -8:01 PM
Bioequivalence Guidance Summary                                                                                                                             PHC331H1

 Parent and/or Metabolite Required?
 For BE studies, measurement of only the parent drug released from the dosage form, rather than the metabolite, is generally recommended. The rationale for this
 recommendation is that concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more
 reflective of metabolite formation, distribution, and elimination. The following are exceptions to this general approach.
 • Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum for an
 adequate length of time. We recommend that the metabolite data obtained from these studies be subject to a confidence interval approach for BE demonstration.
 If there is a clinical concern related to efficacy or safety for the parent drug, we also recommend that sponsors and/or applicants contact the appropriate review
 division to determine whether the parent drug should be measured and analyzed statistically.
 • A metabolite may be formed as a result of gut wall or other presystemic metabolism. If the metabolite contributes meaningfully to safety and/or efficacy, we
 also recommend that the metabolite and the parent drug be measured. When the relative activity of the metabolite is low and does not contribute
 meaningfully to safety and/or efficacy, it does not have to be measured. We recommend that the parent drug measured in these BE studies be analyzed
 using a confidence interval approach. The metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. (1)




 Blinding and Data Analysis
 Subjects with predose plasma concentrations:
 • If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic
 measurements and calculations. We recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
 Data deletion due to vomiting:
 • We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical
 analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time
 during the labeled dosing interval can be deleted. (1)




 Reference Product
 For ANDAs, we also recommend that the BE study be conducted between the test product and reference listed drug using the strength(s) specified in Approved Drug
 Products with Therapeutic Equivalence Evaluations (Orange Book). (1)




                                                                                                                                                     6/12/2013 -8:01 PM
Bioequivalence Guidance Summary                                                                                                                         PHC331H1

 Combining Studies




 REFERENCES
 (1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. U.S. Department of Health
 and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); March 2003. BP Revision 1.
 (2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services. Food and Drug
 Administration. Center for Drug Evaluation and Research (CDER); December 2002. BP.




                                                                                                                                                 6/12/2013 -8:01 PM
                                                                                   BA/BE Guidelines Summary
Regulatory                                         FDA                                                                           TPD                                                                           EMEA
Body

                Unless otherwise indicated by a specific guidance, this guidance               For drugs with uncomplicated characteristics, the following standards-   AUC-ratio: The 90% CI for this measure of relative BA should lie within an
                recommends that the traditional BE limit of 80 to 125 percent for non-         obtained in single dose cross-over comparative bioavailability studies-  acceptance interval of 0.80-1.25. In specific cases of a narrow therapeutic
                narrow therapeutic range drugs remain unchanged for the bioavailability        determine bioequivalence:                                                range the acceptance interval may be tightened. In rare cases a wider
                measures (AUC and Cmax) of narrow therapeutic range drugs. (1)                 a) The 90% confidence interval of the relative mean AUCT of the test to  acceptance range may be acceptable if it is based on sound clinical
                [90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional         reference product should be within 80 percent to 125 percent.            justification.
                PK Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2] (1)                  b) The relative mean measured Cmax of the test to reference product      Cmax-ratio: The 90% CI for this measure of relative BA should lie within an
                                                                                               should be between 80 percent and 125 percent.                            acceptance interval of 0.80-1.25.
                                                                                               These standards must be met on log transformed parameters calculated     The data should be transformed prior to analysis using a logarithmic
Standards for
                                                                                               from                                                                     transformation. (1)
BE: Single
                                                                                               • the measured data, and                                                 PK Parameters: AUCt, AUCinf, Cmax, tmax, AEt, AEinf. For additional
Dose Studies
                                                                                               • data corrected for measured drug content (percent potency of label     information t1/2 and MRT can be estimated. (1)
                                                                                               claim)                                                                   If appropriate to the evaluation the analysis technique for tmax should be
                                                                                               Additional PK Parameters to report: AUCT, AUCI, AUCT, AUCT/AUCI,         non-parametric and should be applied to untransformed data. (1)
                                                                                               Cmax, Tmax, lambda. (1)                                                  For establishing bioequivalence, the 90% confidence interval should lie
                                                                                                                                                                        within the acceptance interval (in most cases, 0.80 – 1.25), the borders
                                                                                                                                                                        being included. The conclusion that products are bioequivalent is based on
                                                                                                                                                                        the overall scientific assessment of the PK studies, not only on meeting the
                                                                                                                                                                        acceptance range. (3)
                For steady-state studies, we recommend that the measurement of total           The 90% confidence interval of the relative mean AUCtau of the test to   Whenever multiple dose studies are performed it should be demonstrated
                exposure be the area under the plasma, serum, or blood concentration-          reference formulation should be within 80% to 125%.                      that steady state has been reached. (2)
                time curve from time zero to time tau over a dosing interval at steady state   The relative mean measured Cmax at steady state of the test to reference PK Parameters: AUCtau, Cmax, Cmin, fluctuation.
                (AUC0-tau), where tau is the length of the dosing interval. (1)                formulation should be within 80% to 125%.
                PK Parameters: Cmin (concentration at the end of a dosing interval), Cav       The relative mean measured Cmin at steady state of the test to reference
                (average concentration during a dosing interval), degree of fluctuation        formulation should not be less than 80%.
                [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] (1)                            [met on both potency uncorrected and corrected data]

                                                                                               PK Parameters: AUCtau, Cmax, Tmax, Cpd, Cmin, fluctuation.
Standards for
                                                                                               For steady-state studies of drugs with uncomplicated characteristics, at
BE: Steady
                                                                                               least three consecutive pre-dose concentration levels (Cpd) are required to
State Studies
                                                                                               provide evidence of steady state. Generally, observations of Cpd for the
                                                                                               test and reference products should be recorded at the same time of the
                                                                                               day. One of these measurements could be taken based on the first sample
                                                                                               of the study day in which a profile over the dosing interval is being
                                                                                               established. Steady state is usually achieved when repeated doses of a
                                                                                               formulation are administered over a period that exceeds five disposition
                                                                                               half-lives of the modified-release form. (6)

                                                                                               Analysis of Tmax, lambda, and fluctuation should be carried out on
                                                                                               the raw scale, while calculations for AUCX, AUCT, AUCtau, AUCI,
                                                                                               Cmin, Cpd, and
                RAPID ONSET:                                                                   Cmax should use the logarithmic (ln) scale. (6)
                                                                                               RAPID ONSET:                                                                   RAPID ONSET:
                An early exposure measure may be informative on the basis of appropriate To date this standard has only been applied to two drugs, gel formulations           Statistical evaluation of tmax only makes sense if there is a clinically
                clinical efficacy/safety trials and/or pharmacokinetic/pharmacodynamic         of ibuprofen and tablet formulations of sumatriptan. This notice serves to     relevant claim for rapid release or action or signs related to adverse
                studies that call for better control of drug absorption into the systemic      clarify that bioequivalence standards for drugs for which an early time of     effects. The non-parametric 90% confidence interval for this measure of
                circulation (e.g., to ensure rapid onset of an analgesic effect or to avoid an onset or rapid rate of absorption is important because of therapeutic or       relative bioavailability should lie within a clinically determined range.
                excessive hypotensive action of an antihypertensive). In this setting, the     toxic effects (for example, an analgesic for rapid relief of pain) are as
                guidance recommends use of partial AUC as an early exposure measure. described in current TPD guidelines and policy statements. In addition, the
                We recommend                                                                   relative mean AUCReftmax of the test to reference formulation should be
                that the partial area be truncated at the population median of Tmax values within 80 to 125%, where AUCReftmax for a test product is defined as the
Rapid Onset
                for the reference formulation. We also recommend that at least two             area under the curve to the time of the maximum concentration of the
Drugs
                quantifiable                                                                   reference product, calculated for each study subject. We reiterate that this
                samples be collected before the expected peak time to allow adequate           notice applies to comparative bioavailability (bioequivalence) studies only.
                estimation of the partial area. (1)                                            Submissions in support of comparative (superiority) claims, such that time
                                                                                               to onset of effect is important, may need additional pharmacokinetic-
                                                                                               pharmacodynamic or clinical data. (4)
              MODIFIED RELEASE:                                                             MODIFIED RELEASE (APPLIES TO SINGLE DOSE):
              For modified-release products submitted as ANDAs, the following studies       PK Parameters: AUCX, AUCT, AUCI, AUCX/AUCI, AUCT/AUCI, Cmax,
              are recommended: (1) a single-dose, nonreplicate, fasting study               Tmax, lambda. For formulations that are likely to accumulate
              comparing the highest strength of the test and reference listed drug          (i.e., AUCX/AUCI < 0.8), safety requires that steady-state studies be
Specifics for product and (2) a food-effect, nonreplicate study comparing the highest       performed in addition to the single-dose studies. Where the AUCX/AUCI
Modified      strength of the test and reference product (see section VI.A). Because        ratio cannot
Release Drugs single-dose studies are considered more sensitive in addressing the           be reliably determined, accumulation must be assumed to occur. (7)
              primary question of BE (i.e., release of the drug substance from the drug
              product into the systemic circulation), multiple-dose studies are generally
              not recommended, even in instances where nonlinear kinetics are present.
              (1)
              Extra PK parameters:
              • Lag-time (tlag) for modified-release products, if present (2)
                                                                                                                                                                          HIGHLY VARIABLE DRUG:
                                                                                                                                                                          A drug product is called highly variable if its intra-individual (i.e. within-
                                                                                                                                                                          subject) variability is greater than 30%. A high CV as estimated from the
                                                                                                                                                                          ANOVA
                                                                                                                                                                          model is thus an indicator for high within-subject variability. However, a
                                                                                                                                                                          replicate design is needed to assess within-subject variability. (3)
                                                                                                                                                                          90% CI of AUC ratio: In rare cases a wider acceptance range may be
                                                                                                                                                                          acceptable if it is based on sound clinical justification.
Standards for                                                                                                                                                             90% CI of Cmax ratio: In specific cases of a narrow therapeutic range the
BE: High                                                                                                                                                                  acceptance interval may be tightened. In certain cases a wider interval may
variability                                                                                                                                                               be
drugs                                                                                                                                                                     acceptable. The interval must be prospectively defined e.g. 0.75-1.33 and
                                                                                                                                                                          justified addressing in particular any safety or efficacy concerns for patients
                                                                                                                                                                          switched between formulations. (1)
                                                                                                                                                                          The NfG states under 3.6.2 that “With respect to the ratio of Cmax the 90%
                                                                                                                                                                          confidence interval for this measure of relative bioavailability should lie
                                                                                                                                                                          within
                                                                                                                                                                          an acceptance range of 0.80 – 1.25. In specific cases, such as a narrow
                                                                                                                                                                          therapeutic range, the acceptance interval may need to be tightened.” The
                                                                                                                                                                          NfG
                                                                                                                                                                          also states that “In certain cases a wider interval may be acceptable. The
                                                                                                                                                                          interval must be prospectively defined, e.g. 0.75 – 1.33, and justified
                                                                                                                                                                          addressing
                                                                                            NON-LINEAR KINETICS:                                                          in particular any safety or efficacy concerns for patients switched between
                                                                                            These requirements must be met in both the fasting and fed states except      formulations”.
                                                                                            where it has been demonstrated that food does not modify bioavailability at   The possibility offered here by the guideline to widen the acceptance
                                                                                            doses within the range of strengths to be marketed. (8)                       range of 0.80 – 1.25 for the ratio of Cmax (not for AUC) should be
                                                                                            The following pharmacokinetic parameters should be calculated from            considered
                                                                                            single dose studies: AUCX, AUCI, Cmax and, where possible, lambda.            exceptional and limited to a small widening (0.75 − 1.33). Furthermore, this
                                                                                            The following parameters should be calculated from steady state studies:      possibility is restricted to those products for which at least one of the
                                                                                            AUCtau, Cmax, Cpd, and Cmin.                                                  following criteria applies:
                                                                                            STANDARDS FOR NON-LINEAR KINETICS DRUGS:                                      1. Data regarding PK/PD relationships for safety and efficacy are adequate
Non-Linear                                                                                  Single Dose: Standards for bioavailability and bioequivalence are those       to demonstrate that the proposed wider acceptance range for Cmax does
Kinetics                                                                                    described in Report A: "Bioavailability of Oral Dosage Formulations of        not
(Report C)                                                                                  Drugs Used for Systemic Effects".                                             affect pharmacodynamics in a clinically significant way.
                                                                                            Chronic Dose: For drugs requiring chronic dose studies the following          2. If PK/PD data are either inconclusive or not available, clinical safety and
                                                                                            bioavailability and bioequivalence standards are required:                    efficacy data may still be used for the same purpose, but these data should
                                                                                            1. The 90% confidence interval of the relative mean AUCtau* of the test to    be specific for the compound to be studied and persuasive.
                                                                                            reference formulation should be within 80 to 125%.                            3. The reference product has a highly variable within-subject bioavailability.
                                                                                            2. The relative mean measured Cmax of the test to reference formulation       Please refer to the Question on highly variable drug or drug products for
                                                                                            should be within 80 to 125%.                                                  guidance on how to address this issue at the planning stage of the
                                                                                            3. The relative mean measured Cmin of the test to reference formulation       bioequivalence trial.
                                                                                            should be within 80 to 125%.                                                  A post hoc justification of an acceptance range wider than defined in the
                                                                                            AUCtau* is defined as the area under the plasma concentration- time curve     protocol cannot be accepted. Information that would be required to justify
                                                                                            after several doses indicating                                                results
                                                                                            "pseudo" steady state. Because of the non-linearity, steady state may be      lying outside the conventional acceptance range at the post hoc stage
                                                                                            difficult to discern.                                                         should be utilised at the planning stage, either for a scientific justification of
                                                                                            These standards must be met on parameters calculated from both the            a
                                                                                            measured data and data corrected for measured drug content. (8)               wider acceptance range for Cmax , or for selecting an experimental
                                                                                                                                                                          approach that allows the assessment of different sources of variability. (3)
               LONG HALF-LIFE DRUGS:                                                            LONG HALF-LIFE DRUGS:                                                          LONG HALF-LIFE DRUGS:
               In a BA or pharmacokinetic study involving an oral product with a long half-     This notice serves to clarify that for drugs which exhibit a terminal          For drugs with a long half-life, relative bioavailability can be adequately
               life drug, adequate characterization of the half-life calls for blood sampling   elimination half-life greater than 24 hours, bioequivalence standards in       estimated using truncated AUC as long as the total collection period is
               over a long period of time. For a BE determination of an oral product with a     comparative                                                                    justified.
               long half-life drug, a nonreplicate, single-dose, crossover study can be         bioavailability studies will be applied to AUC0-72h. For the purpose of        In this case the sample collection time should be adequate to ensure
               conducted, provided an adequate washout period is used. If the crossover         bioequivalence assessment, it will not be necessary to sample for more         comparison of the absorption process. (1)
               study is problematic, a BE study with a parallel design can be used. For         than 72
               either a crossover or parallel study, we recommend that sample collection        hours post-dose, regardless of the half-life. Alternate designs such as
               time be adequate to ensure completion of gastrointestinal transit                parallel studies could be considered. (3)
Long Half-Life (approximately 2 to 3 days) of the drug product and absorption of the drug
               substance. Cmax and a suitably truncated AUC can be used to
               characterize peak and total drug exposure,
               respectively. For drugs that demonstrate low intrasubject variability in
               distribution and clearance, an AUC truncated at 72 hours (AUC0-72 hr) can
               be used
               in place of AUC0-t or AUC0-∞. For drugs demonstrating high intrasubject
               variability in distribution and clearance, AUC truncation warrants caution. In
               such
               cases, we also recommend that sponsors and/or applicants consult the
               appropriate review staff. (1)

                 CRITICAL DOSE DRUGS:                                                           CRITICAL DOSE DRUGS:                                                           CRITICAL DOSE DRUGS:
                 Unless otherwise indicated by a specific guidance, this guidance               1. The 90% confidence interval of the relative mean AUC of the test to         [90% CI of] AUC-ratio: In specific cases of a narrow therapeutic range the
                 recommends that the traditional BE limit of 80 to 125 percent for non-         reference formulation should be within 90.0 to 112.0%; the relevant AUC or     acceptance interval may be tightened.
                 narrow therapeutic range drugs remain unchanged for the bioavailability        AUCs                                                                           [90% CI of] Cmax-ratio: In specific cases of a narrow therapeutic range the
                 measures (AUC and Cmax) of narrow therapeutic range drugs. (1)                 as described in Guidelines A and B are to be determined.                       acceptance interval may need to be tightened. (1)
                                                                                                2. The 90% confidence interval of the relative mean measured Cmax of the
Standards for                                                                                   test to reference formulation should be between 80.0 and 125.0%.
BE: Critical                                                                                    3. These requirements are to be met in both the fasted and fed states.
Dose Drugs                                                                                      4. These standards should be met on log transformed parameters
                                                                                                calculated from the measured data and from data corrected for measured
                                                                                                drug content
                                                                                                (percent potency of label claim).
                                                                                                5. Steady-state studies are not required for “critical dose drugs” unless
                                                                                                warranted by exceptional circumstances. If a steady-state study is required,
                                                                                                the
                                                                                                90% confidence interval of the relative mean measured Cmin of the test to
                 Subjects with predose plasma concentrations:                                   reference formulationinclude all data for all subjects and 125.0%. (6)
                                                                                                The analyses should should also be between 80.0 (see Section 3.4,              The method of analysis should be planned in the protocol. The protocol
                 • If the predose concentration is ≤ 5 percent of Cmax value in that subject,   "Drop-outs and Withdrawal of Subjects from a Study") on measured data.         should also specify methods for handling drop-outs and for identifying
                 the subject’s data without any adjustments can be included in all              Supplementary analyses may also be carried out with selected points or         biologically implausible outliers. Post hoc exclusion of outliers is generally
                 pharmacokinetic measurements and calculations. We recommend that if            subjects initially excluded from the analyses. Such exclusions must be         not accepted. If modelling assumptions made in the protocol (e.g. for
                 the predose value is > than 5 percent of Cmax, the subject be dropped          justified. It is rarely acceptable to exclude more than 5 percent of the       extrapolating AUC to infinity) turn out to be invalid, a revised analysis in
                 from all BE study evaluations.                                                 subjects or more than 10 percent of the data for a single subject-             addition to the planned analysis (if this is feasible) should be presented and
                 Data deletion due to vomiting:                                                 formulation combination. (1)                                                   discussed. (1)
                 • We recommend that data from subjects who experience emesis during
                 the course of a BE study for immediate-release products be deleted from                                                                                       Under 3.6.3 the NfG states that “Post-hoc exclusion of outliers is generally
                 statistical analysis if vomiting occurs at or before 2 times median Tmax. In                                                                                  not accepted” but at the same time acknowledges that “the protocol should
Data to          the case of modified-release products, the data from subjects who                                                                                             also specify methods for identifying biologically implausible outliers”.
Analyze          experience emesis any time during the labeled dosing interval can be                                                                                          Unbiased assessment of results from randomised studies requires that all
                 deleted. (1)                                                                                                                                                  subjects are observed and treated according to the same rules that should
                                                                                                                                                                               be independent from treatment or outcome. In consequence,
                                                                                                                                                                               pharmacokinetic data can only be excluded based on non-statistical
                                                                                                                                                                               reasons that have been either defined previously in the protocol or, at the
                                                                                                                                                                               very least, established before reviewing the data. Acceptable explanations
                                                                                                                                                                               to exclude pharmacokinetic data or to exclude a subject would be protocol
                                                                                                                                                                               violations like vomiting, diarrhoea,
                                                                                                                                                                               analytical failure, etc. The search for such explanations must apply to all
                                                                                                                                                                               subjects in all groups independently of the size of the observed
                                                                                                                                                                               pharmacokinetic
                                                                                                                                                                               parameters or its outlying position. Exclusion of data can never be
                                                                                                                                                                               accepted on the basis of statistical analysis or for pharmacokinetic reasons
                                                                                                                                                                               alone,
                                                                                                                                                                               because it is impossible to distinguish between formulation effects and
                                                                                                                                                                               pharmacokinetic effects. Exceptional reasons may justify post-hoc data
                                                                                                                                                                               exclusion
                                                                                                                                                                               but this should be considered with utmost care. In such a case, the
                                                                                                                                                                               applicant must demonstrate that the condition stated to cause the deviation
                                                                                                                                                                               is present
                                                                                                                                                                               in the outlier(s) only and absence of this condition has been investigated
                                                                                                                                                                               using the same criteria for all other subjects. Results of statistical analyses
                                                                                                                                                                               with
                                                                                                                                                                               and without the group of excluded subjects should be provided. (3)
                We recommend that blood samples be drawn at appropriate times to                 The duration of blood or urine sampling in a study should be sufficient to       The sampling schedule should be planned to provide an adequate
                describe the absorption, distribution, and elimination phases of the drug.       account for at least 80 percent of the known AUC to infinity (AUCI). This        estimation of Cmax and to cover the plasma concentration time curve long
                For most drugs, we recommend that 12 to 18 samples, including a                  period is usually at least three times the terminal half-life of the drug. To    enough to provide a reliable estimate of the extent of absorption. This is
                predose sample, be collected per subject per dose. This sampling can             permit Calculation of the relevant pharmacokinetic parameters, from 12 to        generally achieved if the AUC derived from measurements is at least 80%
Sampling        continue for at least three or more terminal half lives of the drug. The exact   18 samples should be collected per subject per dose. There may be                of the AUC extrapolated to infinity. If a reliable estimate of terminal half-life
Scheme          timing for sample collection depends on the nature of the drug and the           considerable inaccuracies in the estimates of the terminal disposition rate      is necessary, it should be obtained by collecting at least three to four
Criteria        input from the administered dosage form. The sample collection can be            constant if the constant is estimated from linear regression using only a few    samples during the terminal log linear phase. (1)
                spaced in such a way that the maximum concentration of the drug in the           points. To reduce these inaccuracies it is preferable that four or more
                blood (Cmax) and terminal elimination rate constant (λz) can be estimated        points be determined during the terminal log-linear phase of the curve. (1)
                accurately. At least three to four samples can be obtained during the
                terminal log-linear phase to obtain an accurate estimate of λz from linear
                regression. (1)
                An adequate washout period (e.g., more than 5 half lives of the moieties to      The interval should be the same for all subjects and, to account for            Subsequent treatments should be separated by adequate wash out
                be measured) would separate each treatment. (1)                                  variability in elimination rate between subjects, normally should be not less periods.
Washout                                                                                          than 10 times the mean terminal half-life of the drug. (generally, the interval
                                                                                                 between study days should not exceed four weeks). (1,7)

                we recommend a BE study under fed conditions for all orally administered         For uncomplicated drugs in immediate-release dosage forms, if there is a         Subjects should preferably be fasting at least during the night prior to
                immediate-release drug products, with the                                        documented serious safety risk to subjects from single-dose administration       administration of the products. If the Summary of Product Characteristics
                following exceptions:                                                            of the drug or drug product in the absence of food, then an appropriately        of the reference product contains specific recommendations in relation with
                • When both test product and RLD are rapidly dissolving, have similar            designed study conducted in the presence of only a sufficient quantity of        food intake related to food interaction effects the study should be designed
                dissolution profiles, and contain a drug substance with high solubility and      food to prevent the toxicity may be acceptable for purposes of BE                accordingly. (1)
                high permeability (BCS Class I) (see footnote 3), or                             assessment. (5)
                • When the DOSAGE AND ADMINISTRATION section of the RLD label                                                                                                 The recommendations concerning food intake in the SPC are not sufficient
                states that the product should be taken only on an empty stomach, or                                                                                          for regulatory decisions on the adequacy of bioequivalence studies.
                • When the RLD label does not make any statements about the effect of                                                                                         Preferably, the following conditions should be considered separately when
                food on                                                                                                                                                       the SPC recommends administration of the substance together with food
Fasting vs.     absorption or administration. (2)                                                                                                                             intake:
Fed: Single                                                                                                                                                                   1. If the recommendation of food intake in the SPC is based on
Dose            In ANDAs, BE of the test to the RLD is demonstrated in a single dose                                                                                          pharmacokinetic properties such as higher bioavailability, then a
                crossover study. Both treatments should be sprinkled on one of the soft                                                                                       bioequivalence study under fed conditions is generally required.
                foods mentioned in the labeling, usually applesauce. The BE data should                                                                                       2. If the recommendation of food intake is intended to decrease adverse
                be analyzed using average BE and the 90 percent CI criteria should be                                                                                         events or to improve tolerability, a bioequivalence study under fasting
                used to declare BE. If there are questions about other foods, the design,                                                                                     conditions is
                or the analysis of such BE studies, the sponsors and/or applicants should                                                                                     considered acceptable although it would be advisable to perform the study
                contact the Office of Generic Drugs.(2)                                                                                                                       under fed conditions.
                                                                                                                                                                              3. If the SPC leaves a choice between fasting and fed conditions, then
                                                                                                                                                                              bioequivalence should preferably be tested under fasting conditions as this
                                                                                                                                                                              situation
                                                                                                                                                                              will be more sensitive to differences in pharmacokinetics.
                We recommend that food-effect BA and fed BE studies be performed for                                                                                          Different modified release formulations of the same drug substance may
                                                                                                 A second or subsequent market entry MR formulation should be compared The composition of the meal should be described and taken into account,
                all modified release dosage forms.                                               with the Group I or II MR product with which bioequivalence is claimed.      since with respect might sometimes be preferableinfluence of food on the
                                                                                                                                                                              differ a light meal to food interaction. Hence, the to mimic clinical
                                                                                                                                                                              bioavailability
                                                                                                 Both formulations should be administered as single doses. The objective conditions, of oral modified release formulations must be investigated
Fasting vs.                                                                                                                                                                   for safety when the fed state is expected to be less sensitive to
                                                                                                 of these studies is to evaluate the bioequivalence of the test and reference especiallyand efficacy purposes. (2)
Fed: Modified                                                                                    drug products under both fasting and fed conditions. However, safety of      differences in pharmacokinetics. However, for modified release products,
Release                                                                                          the subjects may require that an investigation be conducted after the        a high fat meal
                                                                                                 administration of an appropriate meal at a specified time before taking the is required. For products with release characteristics differing from
                                                                                                 drug. In this case, manufacturers should consult with Health Canada before conventional immediate release (e.g. improved release, dissolution or
                                                                                                 undertaking the study. (7)                                                   absorption), even
                                                                                                 CRITICAL DOSE:                                                               if they cannot be classified as modified release products with prolonged or
                                                                                                 In general BE should be demonstrated under both fasted and fed               delayed release, bioequivalence studies may be necessary in both the
                                                                                                 conditions.                                                                  fasted
                                                                                                                                                                              and fed states. (3)
Fasting vs.
Fed: Critical                                                                                    For complicated drugs in immediate-release dosage form [#5.2] and drugs
Dose                                                                                             in modified-release dosage forms [#5.3], if there is a documented serious
                                                                                                 safety risk to subjects from single-dose administration of the drug or drug
                                                                                                 product in either the absence or presence of food, then an appropriately
                                                                                                 designed study conducted in the indicated condition of use (fed or fasted
                                                                                                 state) may be acceptable for purposes of BE assessment. (5)
                                                                                                 If possible, the study should be conducted in such a way that the subject is
                                                                                                 not aware of which product is administered. Furthermore, the person
                                                                                                 checking for adverse reactions and the person conducting the analysis of
Blinding                                                                                         samples must not know which product was administered. Other individuals
                                                                                                 involved in the administration of the drugs, the surveillance of the patients,
                                                                                                 or the analysis of plasma (or blood, or serum) data should not know which
                                                                                                 product was administered. (1)
                For ANDAs, we also recommend that the BE study be conducted between              • a drug product that has been issued a notice of compliance pursuant to         A 'Reference Product' must be an 'innovator' product. (1)
Reference       the test product and reference listed drug using the strength(s) specified in    section C.08.004 of the Food and Drug Regulations, and is currently
Product         Approved Drug Products with Therapeutic Equivalence Evaluations                  marketed in Canada by the innovator, or
                (Orange Book). (1)                                                               • a drug product acceptable to the Director. (1)
              For BE studies, measurement of only the parent drug released from the         Determination of bioequivalence should be based on data for the parent       In most cases evaluation of bioavailability and bioequivalence will be based
              dosage form, rather than the metabolite, is generally recommended. The        drug.                                                                        upon the measured concentrations of the parent compound. In some
              rationale for this recommendation is that concentration-time profile of the                                                                                situations, however, measurements of an active or inactive metabolite may
              parent drug is more sensitive to changes in formulation performance than aWaiver of the measurement of the parent drug will not be considered,             be necessary instead of the parent compound. Such situations include
              metabolite, which is more reflective of metabolite formation, distribution,
                                                                                        unless concentrations of the parent drug cannot be reliably measured, e.g., cases where the use of a metabolite may be advantageous to determine
              and elimination. The following are exceptions to this general approach.   if the parent drug is not detectable due to rapid biotransformation or           the extent of drug input, e.g. if the concentration of the active substance is
              • Measurement of a metabolite may be preferred when parent drug levels    limitations in available assay methodology. In such instances, the use of        too low to be accurately measured in the biological matrix (e.g. major
              are too low to allow reliable analytical measurement in blood, plasma, or metabolite data may be acceptable. The measured metabolite should be a difficulty in analytical method, product instable in the biological matrix or half-
              serum for an adequate length of time. We recommend that the metabolite    primary (first step) and major one, and appropriate scientific justification for life of the parent compound too short) thus giving rise to significant
              data obtained from these studies be subject to a confidence interval      a waiver of the measurement of the parent drug and the use of metabolite variability.
              approach for BE demonstration. If there is a clinical concern related to  data should be provided. The choice of using the metabolite instead of the
Metabolites   efficacy or safety for the parent drug, we also recommend that sponsors   parent drug is to be clearly stated, a priori, in the objective of the study in  Bioequivalence determinations based on metabolites should be justified in
              and/or applicants contact the appropriate review division to determine    the study protocol.                                                              each case bearing in mind that the aim of a bioequivalence study is
              whether the parent drug should be measured and analyzed statistically.                                                                                     intended to compare the in vivo performance of test and reference
              • A metabolite may be formed as a result of gut wall or other presystemic For the purpose of this guidance, a pro-drug is to be treated as a ‘parent       products. In particular if metabolites significantly contribute to the net
              metabolism. If the metabolite contributes meaningfully to safety and/or   drug’. That is, if the substance released from the dosage form is absorbed activity of an active substance and the pharmacokinetic system is non-
              efficacy, we also recommend that the metabolite and the parent drug be    intact and is reliably measurable in the systemic circulation, it should be      linear, it is necessary to measure both parent drug and active metabolite
              measured. When the relative activity of the metabolite is low and does notused in the assessment of bioequivalence. It is not generally considered         plasma concentrations and evaluate them separately. (1)
              contribute                                                                necessary to measure both
              meaningfully to safety and/or efficacy, it does not have to be measured.  parent drug and metabolite levels for the purpose of bioequivalence              According to the guideline, the only situations where metabolite data can
              We recommend that the parent drug measured in these BE studies be         assessment. However, quantitation of metabolite levels may sometimes be be used to establish bioequivalence are:
              analyzed                                                                  helpful, e.g., to explain extreme values caused by metabolic changes within 1. “If the concentration of the active substance is too low to be accurately
              using a confidence interval approach. The metabolite data can be used to  a subject. In those rare situations where use of drug concentrations in urine measured in the biological matrix, thus giving rise to significant variability”.
              provide supportive evidence of comparable therapeutic outcome. (1)        If justifiable for the assessment of relative bioavailability, only parent drug
                                                                                        is two or more studies have been completed, they may be pooled if certain Comments. Metabolite data can only be used if the Applicant presents
                                                                                        requirements are met.
                                                                                        concentrations may be used. That is, use of metabolite concentrations in         convincing, state-of-theart arguments that measurements of the parent
                                                                                        a) The not considered acceptable in the assessment of bioequivalence. (3 compound
                                                                                        urine issame protocol must be used for all studies.
                                                                                        Specifically,
                                                                                        - DRAFT) this means that the same analytical method is to be used, the are unreliable. Even so, it is important to point out that Cmax of the
                                                                                        blood samples drawn at the same time, and the same lots of the same              metabolite is less sensitive to differences in the rate of absorption than
                                                                                        formulations used.
                                                                                        When a pro-drug is administered, the active component should be                  Cmax of the
                                                                                        b) Two consistency tests must be done on the studies to ensure that
                                                                                        measured. (7 - Report B)                                                         parent drug. Therefore, when the rate of absorption is considered of
Combining                                                                               pooling is meaningful.                                                           clinical importance, bioequivalence should, if possible, be determined for
Studies                                                                                 The first test is the test of equality of the residual mean squares. Take the Cmax of the
                                                                                        ratio of the residual from the first study to the residual for each of the other parent compound, if necessary at a higher dose. Furthermore, when using
                                                                                        studies. (For each ratio, the smaller of the two residuals must be used as       metabolite data as a substitute for parent drug concentrations, the applicant
                                                                                        the denominator.) This ratio is compared to an F statistic, using the            should present data supporting the view that the parent drug exposure will
                                                                                        degrees of freedom associated with the residuals. If the ratio is greater        be reflected by metabolite exposure.
                                                                                        than the 5% F value, the studies may not be combined. The second test is 2. “If metabolites significantly contribute to the net activity of an active
                                                                                        the formulation by study interaction and is carried out as shown in Table 7- substance and the pharmacokinetic system is non-linear”.
                                                                                        A. (1)                                                                           Comments. To evaluate the significance of the contribution of metabolites,
                                                                                                                                                                         relative AUCs and non-clinical or clinical pharmacodynamic activities should
Sources:                                                                                                                                                                 be
              (1) Guidance for Industry: Bioavailability and Bioequivalence Studies for (1) Guidance for Industry: Conduct and Analysis of Bioavailability and           compared with for Proprietary Medicinal Products (CPMP) may befor
                                                                                                                                                                         (1) Committee those of the parent drug. PK/PD modeling - Note useful. If
              Orally Administered Drug Products — General Considerations. U.S.          Bioequivalence Studies - Part A: Oral Dosage Formulations Used for               Guidance significant contribution to activity and pharmacokinetic non-
                                                                                                                                                                         criteria for on the Investigation of Bioavailability and Bioequivalence. CPMP/
              Department of Health and Human Services, Food and Drug Administration, Systemic Effects. Health Products and Food Branch Guidance Document linearity       EWP/QWP/1401/98. London, 26 July 2001.
              Center for Drug Evaluation and Research (CDER); March 2003. BP            (1992).                                                                          are met, then “it is necessary to measure both parent drug and active
              Revision 1.                                                                                                                                                metabolite plasma concentrations and evaluate them separately”. Any
              (2) Guidance for Industry: Food-Effect Bioavailability and Fed            (2) DRAFT GUIDANCE FOR INDUSTRY: Use of Metabolite Data in                       (2) Committee
                                                                                                                                                                         discrepancy for Proprietary Medicinal Products (CPMP) - Note for
              Bioequivalence Studies. U.S. Department of Health and Human Services. Comparative Bioavailability Studies. Health Products and Food Branch,                Guidance on Modified Release Oral and Transdermal Dosage Forms:
                                                                                                                                                                         between the results obtained with the parent compound and the
              Food and Drug Administration. Center for Drug Evaluation and Research     2004/05/05.                                                                      metabolites should be discussed based Evaluation).activities and AUCs. If
                                                                                                                                                                         Section II (Pharmacokinetic and Clinical on relative CPMP/EWP/280/96
              (CDER); December 2002. BP.                                                                                                                                 the July 1999.
                                                                                                                                                                         28 discrepancy
                                                                                        (3) NOTICE TO INDUSTRY: Bioequivalence Requirements for Long Half- (3) CHMP EFFICACY WORKING PARTY) THERAPEUTIC SUBGROUP
                                                                                                                                                                         lies in Cmax , the results of the parent compound should usually prevail.
                                                                                        life Drugs. file 05-113899-750. June 22, 2005.                                   ON PHARMACOKINETICS (EWP-PK): Questions & Answers on the of the
                                                                                                                                                                         Pooling of the plasma concentrations or pharmacokinetic parameters
                                                                                                                                                                         parent drug and its metabolite for Guideline; EMEA/CHMP/EWP/40326/
                                                                                                                                                                         Bioavailability and Bioequivalencecalculation of bioequivalence is not
                                                                                                                                                                         2006; London, 27 July 2006
                                                                                                                                                                         acceptable. (3)
                                                                                        (4) NOTICE TO INDUSTRY: Bioequivalence Requirements for Drugs for
                                                                                        Which an Early Time of Onset or Rapid Rate of Absorption Is Important
                                                                                        (rapid onset drugs). 05-113913-859. June 22, 2005.
                                                                                        (5) GUIDANCE FOR INDUSTRY: Bioequivalence Requirements:
                                                                                        Comparative Bioavailability Studies Conducted in the Fed State. Health
                                                                                        Products and Food Branch. 05-114865-164. July 21, 2005.
                                                                                        (6) GUIDANCE FOR INDUSTRY: Bioequivalence Requirements: Critical
                                                                                        Dose Drugs. Health Products and Food Branch. 06-112871-930. June 7,
                                                                                        2006.
                                                                                        (7) GUIDANCE FOR INDUSTRY: Conduct and Analysis of Bioavailability
                                                                                        and Bioequivalence Studies - Part B: Oral Modified Release Formulations.
                                                                                        Health Products and Food Branch Guidance Document. 1996.
(8) Report on Bioavailability of Oral Dosage Formulations of Drugs Used
for Systemic Effects. Report C: Report on Bioavailability of Oral Dosage
Formulations, Not in Modified Release Form, of Drugs Used for Systemic
Effects, Having Complicated or Variable Pharmacokinetics. Expert
Advisory Committee on Bioavailability. Health Protection Branch,
December 1992.
Canadian BA/BE Drug Classification System
Critical Dose Drugs
Cyclosporine                 C - Critical Dose Drug
Digoxin                      C - Critical Dose Drug
Flecainide                   C - Critical Dose Drug
Lithium                      C - Critical Dose Drug
Phenytoin                    C - Critical Dose Drug
Sirolimus                    C - Critical Dose Drug
Tacrolimus                   C - Critical Dose Drug
Theophylline                 C - Critical Dose Drug
Warfarin                     C - Critical Dose Drug

Drugs with Non-Linear Kinetics
Acetylsalicylic acid         C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Acyclovir                    C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Carbamazepine                C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Cephalosporins               C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Disopyramide                 C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Fluorouracil                 C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Glucocorticosteroids         C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Griseofulvin                 C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Levodopa                     C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Phenytoin                    C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Propranolol                  C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Rifampin                     C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Valproic acid                C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Verpamil                     C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
FDA Special Guidances/Exceptions: Bioequivalence
FDA Special Guidances:
Clozapine                  Steady-state study in patients required at 100 mg. See http://www.fda.gov/CDER/GUIDANCE/6077
Potassium Chloride         Steady-state study required. See http://www.fda.gov/CDER/GUIDANCE/old195fn.pdf

FDA Exceptions:
The following drugs are defined by the 2008 FDA Orange Book as, "DRUG PRODUCTS
WHICH MUST DEMONSTRATE IN VIVO BIOAVAILABILITY
ONLY IF PRODUCT FAILS TO ACHIEVE ADEQUATE DISSOLUTION"
Source: http://www.fda.gov/cder/orange/obannual.pdf
www.fda.gov/CDER/GUIDANCE/6077fnl.pdf
 IDANCE/old195fn.pdf

				
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